Squalene, Olive Oil, and Cancer Risk: a Review and Hypothesis
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Vol. 6, 1101-1103, December 1997 Cancer Epidemiology,Blornarkers & Prevention 1101 Review Squalene, Olive Oil, and Cancer Risk: A Review and Hypothesis Harold L. Newmark’ of unsaturated fatty acids. In Italy, about 80% of edible oil is Strang Cancer Research Laboratory, The Rockefeller University, New York, olive oil,2 suggesting a protective effect of olive oil intake. In New York 10021, and Laboratory for Cancer Research, College of Pharmacy, another Italian case-control study of diet and pancreatic cancer Rutgers University, Piscataway, New Jersey 08855-0789 (8), increased frequency of edible oil consumption was associ- ated with a trend toward decreased risk. Edible oil in Italy consists of about 80% olive oil, thus suggesting a protective Abstract effect of olive oil in pancreatic cancer.2 Epidemioiogical studies of breast and pancreatic cancer Animal studies on fat and cancer have generally shown in several Mediterranean populations have demonstrated that olive oil either has no effect or a protective effect on the that increased dietary intake of olive oil is associated with prevention of a variety of chemically induced tumors. Olive oil a small decreased risk or no increased risk of cancer, did not increase tumor incidence or growth, in contrast to corn despite a higjier proportion of overall lipid intake. and sunflower oil, in some mammary cancer models (9 -1 1) and Experimental animal model studies of high dietary fat also in colon cancer models (12, 13), although in an earlier and cancer also indicate that olive oil has either no effect report, olive oil exhibited mammary tumor-promoting proper- or a protective effect on the prevention of a variety of ties similar to that ofcorn oil (14), in contrast to the later studies chemically induced tumors. As a working hypothesis, it is (15). proposed that the high squalene content of olive oil, as The protective or, at the least, nonpromoting activity of compared to other human foods, is a major factor in the olive oil is often ascribed to its high content (about 72%) of the cancer risk-reducing effect of olive oil. Experiments in monoenoic unsaturated fatty acid oleic acid (C18:l, o9). But vitro and in animal models suggest a tumor-inhibiting this fatty acid is also found in the fat of beef and poultry in the role for squalene. A mechanism is proposed for the range of 30-45% of the fat and is also found in appreciable tumor-inhibitory activity of squalene based on its known levels in other vegetable oils, such as corn (30%), palm (43%), strong inhibitory activity of 3-hydroxy-fi-methylg1utaryl- peanut (49%), soybean (25%), and sunflower seed (33%; Ref. CoA reductase catalytic activity in vivo, thus reducing 16). The other fats and oils rich in oleic acid are largely farnesyl pyrophosphate availability for prenylation of the associated with increased risk of colon and breast cancer in ras oncogene, which relocates this oncogene to cell humans and generally act as promoters of chemically induced membranes and is required for the signal-transducing tumors in rodents. Thus it seems that the monoenoic unsatur- function of ras. ated fatty acid (oleic acid) content of olive oil cannot account for its protective effect or lack of promotion effect in cancer development. Introduction A recent report of a case-control study of adipose tissue Certain epidemiological studies suggest a cancer-protective ef- stores of individual monounsaturated fatty acids in relation to fect of dietary olive oil relative to other types of nonmarine fat breast cancer in women also suggest that the oleic acid in olive sources. In Greece, women with approximately 40% of energy oil does not account for any protective property of this oil (17). intake from fat, mainly as olive oil, have a breast cancer rate of A consideration was made of other components unique to only about one-third that of United States women, who have olive oil, qualitatively or quantitatively different from other fats until recently also consumed about 40% of energy from fat and oils, as a possible explanation for its protective or nonpro- (1-3). A case-control study in Spain showed a reduced risk for moting effects. Squalene, at up to 0.7%, is uniquely high in breast cancer in women with the highest olive oil consumption olive oil as compared to other common human food fats and (4). In a large case-control study in Greece, a similar lack of oils (18, 19). Other vegetable oils and animal fats are consid- overall association with total fat intake was seen, but breast erably lower, in the range of 0.002-0.03% (18) squalene con- cancer risk was 25% lower in women consuming olive oil more tent. Food-regulatory agencies often rely on the squalene con- than once a day (5). In another case-control study in Spain (6), tent to determine the purity of commercial olive oil. Squalene women in the highest third of monounsaturated fat intake is a hydrocarbon of the triterpene type containing six isoprene (largely from olive oil) had reduced risk of breast cancer units with a pleasant, bland taste. It is a key intermediate in the (relative risk = 0.30; 95% confidence interval, 0.1-0.8). A biosynthetic pathway to steroids in both plants and animals. recent report of a case-control study performed in Italy (7) Thus, it can be considered as almost ubiquitous in most plant indicated a decreased risk of breast cancer with increased intake and animal cells, although at enormously different levels. There are only a few reports of an inhibiting effect of squalene itself in rodent cancer models. Van Duuren and Goldschmidt noted that squalene as well as oleic acid applied Received 6/1 1/97; revised 8/5/97; accepted 8/11/97. The costs of publication of this article were defrayed in part by the payment of topically to mouse skin completely inhibited benzo(a)pyrene- page charges. This article must therefore be hereby marked advertisement in induced skin carcinogenicity (20). o-Limonene only partly in- accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom requests for reprints should be addressed, at Strang Cancer Research Laboratory, The Rockefeller University, 1230 York Avenue, New York, NY 10021. 2 C LaVeccia, personal communication. Downloaded from cebp.aacrjournals.org on September 24, 2021. © 1997 American Association for Cancer Research. 1102 Review: Squalene, Olive Oil, and Cancer Risk hibited skin tumors in the same experiment. In a later study, carcinomas, in which up to 90% are associated with activated Murakoshi et a!. (21) reported that topically applied squalene ras oncogene mutations (28). All these tumors represent po- markedly suppressed the promoting effect of 12-O-tetradeca- tential targets for squalene use as a chemopreventive agent. noylphorbol-13-acetate on mouse skin tumors initiated with Increased dietary squalene intake could theoretically aug- 7,12 dimethylbenz(a)anthracene. In a recent study, we demon- ment cholesterol and bile acid production, resulting in enhanced strated potent inhibition of aberrant hyperproliferation in a atherosclerotic disease. However, a few studies in rabbits and mammary epithelial cell line in vitro (22). In another recent humans indicate that a high intake does not seem to be asso- study using 1% squalene in the diet of rats treated with ciated with a high risk ofatherosclerosis. Kritchevsky et a!. (32) azoxymethane, a 45% suppression of induced aberrant crypt fed 3% squalene in a high-cholesterol diet to rabbits for 14 foci was seen.3 This latter study, to my knowledge, is the first weeks, who failed to develop more atheromas than similar experimental demonstration of the inhibitory action of dietary cholesterol-fed controls. Our recent study also indicates that 1% squalene on carcinogenesis. Other studies on the antitumor squalene in the diet had no effect on serum cholesterol in rats.3 activity of squalene have been reported in Japan (23-25). Strandberg et a!. fed 900 mg of squalene daily to humans for In rats given 1% squalene in the diet for 5 days, serum 7-30 days, demonstrating about 60% absorption with a 17-fold squalene rose about 20-fold. This was accompanied by a strong increase in serum squalene, but produced no consistent in- inhibition (about 80%) of HMG-CoA4 reductase activity in creases in serum cholesterol levels (33). However, these short- hepatic microsomes (26). It is not clear whether this inhibition term feeding studies are insufficient to fully answer questions stems from squalene itself or one or more of its metabolites, of long-term effects of higher-than-normal dietary squalene such as sterols and their oxygenated derivatives (27) produced intake on metabolism of cholesterol and other steroids, as well endogenously. Inhibition of HMG-CoA reductase activity, the as adequacy of biosynthesis of ubiquinones, heme a, and doli- rate-limiting control step in the normal biosynthetic pathway to chols for normal cell function. cholesterol, presumably also reduces the levels of a series of Squalene in humans is supplied by both endogenous bio- intermediates between HMG-CoA reductase and cholesterol synthesis and dietary sources. The Rockefeller University (27) including mevalonate, geranyl pyrophosphate, and FPP. group(18) measured squalene in normal human tissues and IPP is a source for the biosynthesis of ubiquinone, heme a, plasma and found it to be widely distributed, but at great dolichol, and particularly for the prenylation (farnesylation) of variations in level. Sebum was reported to contain 12% squa- certain oncogenes. Many oncogenes such as ras are proteins lene, and adipose tissue contained 0.01-0.04% squalene, with produced in the aqueous environment of the cell cytosol but other tissues having lower levels. Plasma squalene levels rose require relocation to the lipophilic cell plasma membrane for strikingly with increased dietary squalene.